While a statistical gene-gene interaction does not necessarily entail an epistatic interaction, it is interesting to note that the TGF-b/Smad3 signaling pathway has an important role in regulating glucose and energy homeostasis and that Smad3-deficient mice are protected from diet-induced obesity and diabetes [77]. This evidence concerns the gene TGFB1 and obesity due to melanocortin 4 receptor deficiency.